The balance between immune responses mediated by type 1 and type 2 T helper lymphocytes represents one of the fundamental mechanisms for maintaining immunological homeostasis in the human organism. When this delicate balance is compromised, doors open to many pathologies ranging from autoimmune diseases to chronic allergic conditions. Th1 lymphocytes are responsible for cell-mediated response and primarily produce interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, activating macrophages and cytotoxic T lymphocytes to eliminate intracellular pathogens such as viruses and bacteria. On the other side of the immunological spectrum, Th2 lymphocytes orchestrate humoral response through the production of interleukins such as IL-4, IL-5, IL-6, IL-10, and IL-13, stimulating B lymphocytes to produce antibodies and activating eosinophils and mast cells to counter extracellular parasites.
When Th1 response prevails, with elevated levels of interferon-gamma and reduced IL-4, a condition occurs that can lead to the development of organ-specific autoimmune diseases such as Hashimoto's thyroiditis, Crohn's disease, type 1 diabetes, and rheumatoid arthritis. Conversely, Th2 dominance, characterized by low levels of interferon-gamma and high IL-4, is associated with immediate allergic reactions such as allergic rhinitis, asthma, atopic dermatitis, and other atopic manifestations. This imbalance can also favor chronic infections and some tumor forms, creating a permissive immunological environment for the progression of these pathologies. The complexity of this system is further amplified by the presence of other lymphocyte subpopulations such as Th17, responsible for defense against bacteria and fungi but involved in autoimmune diseases when hyperactivated, and regulatory T lymphocytes that maintain immunological tolerance.
Sericin as a selective modulator of Th1 and Th2 responses
Recent research has identified in sericin, the globular protein that coats fibroin filaments in Bombyx mori silkworm cocoons, an interesting capacity to selectively modulate the balance between Th1 and Th2 responses. A study published in Frontiers in Bioengineering and Biotechnology demonstrated that low molecular weight sericin, obtained through high temperature and pressure extraction methods, presents particularly significant immunomodulatory properties. Researchers observed that macrophages cultured with low molecular weight sericin at a concentration of 0.1 milligrams per milliliter showed an improved inflammatory response, evidenced by upregulation of CXCL9, IL12A, BMP7, and IL-10, cytokines that favor the balance between Th1 and Th2.
The peculiar characteristic of this modulation resides in sericin's capacity to simultaneously stimulate both IL-12, which promotes the differentiation of Th1 lymphocytes and natural killer cells to initiate host defense and inflammation, and IL-10, which acts as an anti-inflammatory agent responding to Th2-producing cells to maintain immune balance. This bidirectional mechanism allows the development of a balance between Th1 and Th2 that is beneficial for the balancing of inflammation, regeneration, and remodeling of damaged tissues. During this dynamic homeostasis, the relative suppression of Th1 cells through the relative increase in Th2 activity represents the key mechanism for maintaining or restoring balance in a compromised immune system. Studies have also confirmed that sericin tends to induce M2 activation in macrophages, along with classic M1 activation, as demonstrated by increased expression of the M2 marker Arg-1.
Therapeutic applications in psoriasis
Psoriasis represents particularly fertile ground for evaluating sericin's immunomodulatory potential. This chronic autoimmune pathology, which affects between 0.09 and 11.4% of the world population, is characterized by hyperactivation of the interleukin-23/Th17 axis that triggers an inflammatory cascade with abnormal keratinocyte proliferation and formation of erythematous plaques. Studies conducted on animal models of induced psoriasis demonstrated that 10% sericin produces therapeutic effects comparable to those of betamethasone and calcitriol, significantly reducing epidermal thickness and improving histopathological characteristics of psoriatic lesions.
The anti-inflammatory activity of sericin in psoriasis manifests through decreased expression of chemokine CCL20, a crucial mediator in recruiting inflammatory cells into psoriatic plaques. Proteomic analyses revealed that sericin reduces cytokine production by Th17 cells by interfering with the JAK-STAT signaling pathway, a fundamental pathway in psoriasis pathogenesis. Furthermore, sericin treatment modulates immune response through upregulation of galectin-3, a beta-galactoside-binding protein involved in immune regulation, and downregulation of sphingosine-1-phosphate lyase 1, an enzyme that influences lymphocyte trafficking and inflammatory response.
A particularly interesting study evaluated the combination of sericin with naringin, a flavonoid extracted from citrus fruits, on human peripheral blood mononuclear cells isolated from patients with psoriasis. Results confirmed the superior activity of the naringin-sericin combination compared to single compounds in downregulating proinflammatory cytokines IL-6, IL-12p40, IL-23, and TNF-alpha, all implicated in early inflammatory mechanisms of psoriatic pathogenesis. Sericin demonstrated inhibitory capabilities on interferon-gamma, IL-10, and TNF-alpha, confirming its role as an immunological modulator capable of acting on different fronts of inflammatory response. Sericin-coated polymeric films showed non-irritating properties and capacity to alleviate eczema histology through depletion of beta-defensin, caspase-3 and -9, TNF-alpha, CCL-20, IL-1beta, IL-17, TGF-beta, and Wnt expression, reducing keratinocyte proliferation through the mTOR pathway and epidermal inflammation via IL-17 signaling.
Atopic dermatitis and cutaneous barrier modulation
In atopic dermatitis, a condition characterized by Th2 dominance with elevated IgE production and eosinophilic infiltration, sericin demonstrated capacity to significantly improve cutaneous barrier functionality and modulate altered immune response. Studies conducted on NC/Nga mice, a recognized animal model of atopic dermatitis, evidenced that dietary supplementation with 1% sericin for ten weeks increases epidermal levels of hydration, total filaggrin, and free amino acids, essential components of skin's natural moisturizing factors. Sericin increased expression of PPARgamma, peptidylarginine deiminase-3, and caspase-14, proteins involved in filaggrin expression and degradation processes, bringing these parameters to levels comparable to those of normal mice.
The protein also demonstrated reduction in production of allergic chemokines CCL8 and CCL18, which recruit immune cells such as dendritic cells, monocytes, macrophages, mast cells, eosinophils, and basophils involved in allergic immune responses, particularly in atopic dermatitis. Simultaneously, sericin increases production of anti-inflammatory cytokines such as IL-4, IL-10, and TGF-beta, preserving a state of immunological tolerance that modulates the degree of inflammation. This tolerogenic effect is particularly relevant because it acts directly on melanocytes, dendritic cells, and artificial skin, reducing tyrosinase activity and limiting melanin production, a secondary phenomenon to cutaneous inflammation that can lead to post-inflammatory hyperpigmentation.
Topical formulations containing sericin in hydrogel showed superior intradermal penetration capacity when combined with functional peptides, allowing administration of small interfering RNA directed against RelA, an important subdomain of nuclear factor kappa-B, with therapeutic effects in murine models of atopic dermatitis. Sericin's versatility as a biocompatible biomaterial makes it particularly suitable for topical formulations requiring both pharmacological carrier properties and intrinsic therapeutic activity. Studies on emulgels containing sericin and tamanu oil for topical administration of levocetirizine revealed superior therapeutic enhancement compared to conventional therapies, with reduction in scratching frequency and erythema score in animal models of induced atopic dermatitis.
Molecular mechanisms and signaling pathways involved
At the molecular level, sericin's immunomodulatory activity is expressed through interference with multiple cellular signaling pathways that regulate proliferation, survival, and cellular motility. The mTOR pathway, which plays a fundamental role in regulating epidermal proliferation and inflammation in conditions such as psoriasis, atopic dermatitis, pemphigus, acne, cutaneous T-cell lymphoma, and melanoma, is significantly downregulated by sericin treatment. This modulation allows control of excessive keratinocyte proliferation, a central problem in hyperproliferative cutaneous pathologies. Parallelly, sericin influences the MAPK/ERK pathway, a main signaling pathway for cellular proliferation similar to PI3-K/Akt and mTOR, contributing to corneal resolution and wound healing.
Interference with the JAK-STAT pathway represents another key mechanism through which sericin exerts its anti-inflammatory and immunomodulatory effects. This signaling pathway is crucial for cytokine signal transduction and for Th17 cell differentiation, whose hyperactivation is implicated in the pathogenesis of numerous autoimmune diseases. By blocking this signaling cascade, sericin reduces production of proinflammatory cytokines derived from Th17, such as IL-17A, IL-17F, IL-21, IL-22, and IL-26, which have a critical role in psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. IL-17 in particular promotes expression of S100A8 and S100A9 genes as alarm signals during inflammatory response of keratinocytes in psoriasis.
Apoptosis modulation represents a further aspect of sericin's mechanism of action. Apoptotic dysfunction is considered a key factor in various cutaneous diseases, particularly in psoriasis, where it leads to excessive proliferation and abnormal keratinocyte differentiation. Sericin decreases acanthosis, hyperkeratosis, and epidermal thickening in conjunction with downregulation of caspase-3 and -9, apoptosis executor enzymes whose overexpression plays a fundamental role in psoriasis pathogenesis and is correlated with the onset of psoriatic cutaneous lesions. These results indicate that sericin inhibits keratinocyte proliferation not only through its anti-inflammatory and antioxidative properties but also through regulation of epidermal apoptosis.
Molecular weight and immunomodulatory properties
Sericin's molecular weight emerges as a determining factor for its immunomodulatory efficacy and safety in biomedical applications. Native sericin presents a wide spectrum of molecular weights, varying from fractions with molecular weight exceeding 400 kilodaltons to peptides with weight below 10 kilodaltons, commonly under 5 kilodaltons. Scientific evidence revealed that water-soluble proteins with high molecular weight, approximately between 10 and 50 kilodaltons, comprise the majority of allergens, while allergens with molecular weight around 100 kilodaltons are strongly associated with atopic dermatitis. This observation prompted researchers to optimize extraction of low molecular weight sericin to minimize the risk of allergic reactions and maximize therapeutic efficacy.
Extraction methods significantly influence both molecular weight and biological properties of obtained sericin. Extraction via autoclave at high temperature and pressure allows obtaining low molecular weight fractions under 10 kilodaltons, confirmed through MALDI-TOF mass spectrometry and liquid chromatography coupled with mass spectrometry. These low molecular weight fractions demonstrate excellent biocompatibility with both macrophages and human adipose stem cells, maintaining cellular viability above 80% and showing improved immunomodulatory properties compared to high molecular weight fractions. Low molecular weight sericin can be absorbed more rapidly and provide nutritive substrates for wound healing, representing a safer and more effective therapeutic option.
Extraction with urea represents another method that allows obtaining sericin with specific chemical-physical characteristics while maintaining the three-dimensional structure and natural bioadhesive properties of the protein. This form of sericin shows strong binding capacity to hydrophobic skin proteins, particularly to keratin of the cutaneous layer, recreating the affinity it had with fibroin in natural silk. On one hand it protects cells, on the other it stimulates keratinocytes themselves to produce collagen, thus contributing to regeneration of damaged cutaneous tissue. Sericin's high capacity to retain water molecules makes it a natural protein with unparalleled moisturizing effect, giving skin the characteristic sensation of silk: soft yet resistant.
Future perspectives and development of therapeutic formulations
Scientific evidence accumulated in recent years outlines a promising future for sericin as an immunomodulatory agent in autoimmune and allergic pathologies, but also highlights the need for further studies to optimize therapeutic formulations and validate clinical efficacy in human beings. Currently, most research has focused on preclinical in vitro and in vivo models on animals, which provided extremely encouraging results but require confirmation through randomized controlled clinical studies on human patients. Development of appropriate pharmaceutical formulations represents a crucial challenge, considering the need to stabilize sericin, guarantee optimal cutaneous penetration, and possibly combine it with other active principles to enhance therapeutic efficacy.
Formulations in emulgel, hydrogel, and polymeric films demonstrated promising sericin delivery capabilities, allowing controlled release and effective intradermal penetration. Combination with functional peptides, as demonstrated in studies on siRNA administration for atopic dermatitis, opens perspectives for targeted therapies that exploit both carrier properties and intrinsic therapeutic activity of sericin. Thin films coated with sericin fabricated from silk fibroin through photocrosslinking represent an interesting innovation, offering biocompatibility, mechanical resistance, flexibility, and adhesive properties useful for application on psoriatic plaques or eczematous lesions. These formulations could be further optimized through precise surface patterning to provide targeted spatial and temporal application of sericin.
Long-term safety and pharmacokinetic and pharmacodynamic profiles of sericin in human beings remain areas requiring deepening before large-scale clinical introduction. Toxicological studies conducted so far, which include hematological parameters and blood clinical chemistry, showed generally favorable safety profiles, with some slightly elevated hepatic parameters that could represent contraindications for use of sericin, calcitriol, and dexamethasone in psoriasis treatment, especially at high concentrations or with prolonged use. Evaluation of sericin immunogenicity in diverse human populations and determination of optimal doses for different therapeutic indications represent priority research objectives. Furthermore, comparative efficacy studies with standard therapies, cost-effectiveness evaluations, and quality of life analyses of patients treated with sericin-based formulations will provide crucial information for clinical implementation of this promising biomaterial in the therapeutic armamentarium against chronic autoimmune and allergic pathologies.
