NLRP6 drives cutaneous wound healing during Staphylococcus aureus infection in mice

Infection is a major complication of wound healing worldwide, with Staphylococcus aureus being the most isolated bacterial species from infected wounds. Pattern recognition receptors, such as the NOD-like receptor family (NLRs), play crucial roles in coordinating subsequent stages of wound-healing via specific cells activation through the production of cytokines, such as IL-1β, whose release is strongly dependent on inflammasome complex assembly and is critical for controlling the bacterial load. This study investigated if the NOD-like receptor family pyrin domain-containing 3 (NLRP3), NLRP6, and NLRP12 inflammasomes have a specific role in skin infections and wound healing.

To investigate the role of these NLRs members in infected wounds, Nlrp3-deficient (Nlrp3^-/-), Nlrp6^-/-, and Nlrp12^-/- mice were subjected to a full-thickness wound model followed by topical infection with S. aureus (2.5 × 10⁶ CFU/100 μL).

Interestingly, only genetic ablation of NLRP6 resulted in a significant delay in wound closure. Nlrp6^-/- mice exhibited significantly reduced IL-1β production and impaired extracellular matrix deposition (ECM), with decreased type I and III collagen fibers and fibronectin levels. Moreover, Nrlp6-deficient dermal fibroblasts displayed delayed migratory capacity and reduced cytokine production, such as IL-1β and CXCL-1. Notably, Nlrp6 genetic ablation did not affect bacterial load or leukocyte infiltration frequencies.

These findings support a role for NLRP6 in the regulation of ECM, highlighting it as a potential therapeutic target for chronic wounds and fibrotic skin disorders.