Tristetraprolin expression by keratinocytes controls local and systemic inflammation

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Tristetraprolin (TTP) is an RNA-binding protein crucial for regulating cytokine mRNA stability and controlling inflammation.
• TTP deficiency in myeloid cells is linked to inflammatory syndromes, but its role in skin-resident cells remains unclear.
• Current understanding attributes TTP-deficiency phenotypes primarily to myeloid cell dysfunction.

Purpose of the Study:

• To investigate the role of TTP in keratinocytes in the context of inflammatory skin diseases.
• To determine if keratinocyte-specific TTP deletion exacerbates or modifies inflammatory phenotypes.
• To elucidate the contribution of keratinocyte-derived cytokines to psoriasis and related pathologies.

Main Methods:

• Generation of conditional knockout mice with TTP deleted specifically in keratinocytes (Zfp36ΔEP mice).
• Assessment of inflammatory responses in an imiquimod-induced psoriasis model.
• Analysis of spontaneous development of skin and systemic inflammatory pathologies in Zfp36ΔEP mice.
• Investigation of the role of keratinocyte-derived TNF in driving disease pathogenesis.

Main Results:

• Keratinocyte-specific TTP deletion (Zfp36ΔEP) led to exacerbated inflammation in the imiquimod-induced psoriasis model.
• Zfp36ΔEP mice spontaneously developed systemic inflammation, psoriatic-like skin lesions, and dactylitis.
• Keratinocyte-derived TNF production was identified as a key driver of these pathological features.

Conclusions:

• TTP plays a critical, keratinocyte-intrinsic role in preventing spontaneous inflammatory skin diseases.
• Dysregulation of TTP in keratinocytes contributes significantly to psoriasis and related arthritis pathogenesis.
• These findings reveal a novel mechanism in the initiation and progression of inflammatory conditions, expanding current knowledge beyond myeloid cell involvement.