GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1\u2013Cxcr2 axis

Zhen-Zhen Liu,Xiao-Qi Lin,Shi-Qing Yan,Ke Ma,Yong-Jun Yang,Feng-Hua Zhou,Wei Chen,Yu Gao

doi:10.1186/s13567-021-00937-7

Abstract

Gasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1β secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1–Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1β production, the critical role of IL-1β was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1β production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus. Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1–Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1–Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.

Highlights

Staphylococcus aureus is highly pathogenic and can cause a wide range of clinical infections in both humans and domestic animals, leading to a major impact on public health and agriculture [1, 2]
Gasdermin D (GSDMD) contributes to host protection against S. aureus skin infection To evaluate the role of GSDMD in cutaneous host defence against S. aureus infection, we first compared the skin self-healing ability between the WT and GSDMD−/− mice
The abscess structure from the GSDMD−/− mice was more severe than that from the WT mice on day 2 post-infection (Figure 1D). These results suggested that GSDMD plays an important role in protection against S. aureus skin infection

Summary

Introduction

Staphylococcus aureus is highly pathogenic and can cause a wide range of clinical infections in both humans and domestic animals, leading to a major impact on public health and agriculture [1, 2]. The high burden of S. aureus among human and animal hosts is coupled with the well-known ability of this zoonotic pathogen to become resistant to antibiotics. Due to increasing drug resistance, current effective antibiotics continuously show decreased. Innate immunity is involved in the early recognition and elimination of invading pathogens. Sensing pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) enables host cells to categorize microbial invaders and to initiate appropriate host defence responses. An increased understanding of the innate immune mechanisms during S. aureus infection will help identify novel prevention and therapeutic strategies

Methods

Results

Conclusion