Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes.

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Increased expression of S100A8 (A8) and S100A9 (A9) alarmins and Calprotectin (CP) is observed in inflammatory skin diseases like Atopic Dermatitis (AD).
• The precise functional impact of elevated A8 and A9 in local and systemic disease manifestations remains unclear.

Purpose of the Study:

• To investigate the cell- and tissue-specific roles of A8 and A9 in the pathogenesis of inflammatory skin diseases.
• To elucidate the functional consequences of A8 and A9 on skin inflammation, epidermal differentiation, and systemic complications.

Main Methods:

• Utilized genetically engineered mouse models, specifically the JunB^∆ep model for AD.
• Performed targeted gene inactivation of A9 or A8 in epidermal cells and neutrophils.
• Analyzed local skin and systemic effects, including inflammation, bone loss, and digit pathology.

Main Results:

• Epidermal A9 inactivation aggravated experimental skin inflammation, while epidermal A8 inactivation ameliorated it.
• Inactivation of A9 in neutrophils or all cells improved skin inflammation and epidermal differentiation.
• Complete A9 knockout worsened systemic neutrophilic inflammation and bone loss, with increased A8 in digits leading to bone destruction.

Conclusions:

• Site- and cell-type-specific expression of A8 and A9 differentially modulates chronic skin and systemic inflammation.
• These proteins impact skin differentiation and the musculoskeletal system, suggesting distinct therapeutic targets.
• Targeting the divergent functions of A8 and A9 may offer novel strategies for treating inflammatory skin diseases and associated systemic complications.