NLRC3 promotes host resistance against Pseudomonas aeruginosa-induced keratitis by promoting the degradation of IRAK1

Abstract

Pseudomonas aeruginosa (PA)-induced keratitis is one of the most common and destructive bacterial diseases. The pathogenesis of PA infections is closely associated with excessive inflammatory responses. Nucleotide oligomerization domain (NOD)-like receptor (NLR) family with caspase activation and recruitment domain (CARD) containing 3 (NLRC3) protein has been implicated as a negative regulator of inflammation and antiviral response, but the role of NLRC3 in PA-induced keratitis has not been described. In the present study, we investigated the effects of NLRC3 in PA-induced keratitis and explored the underlying mechanism. We found that the expression of NLRC3 was decreased in mouse corneas and macrophages after PA infection. Overexpr-ession of NLRC3 significantly attenuated disease progression, inhibited the activation of nuclear factor-κB signaling and decreased the production of pro-inflammatory cytokines after PA infection. Furthermore, overexpression of NLRC3 promoted K48-linked polyubiquitination and degradation of interleukin-1 receptor-associated kinase 1 (IRAK1). Taken together, we demonstrated that NLRC3 has an anti-inflammatory effect on PA-induced keratitis, which may provide an improved understanding of host resistance to PA infection.

USP22 promotes pro-inflammatory responses in Pseudomonas aeruginosa-induced keratitis by targeting TRAF6

“…In the current study, we revealed that silencing of USP22 suppressed phosphorylation level of p65 and IκBα, which indicated USP22 could promote NF-κB activation, therefore increased the pro-inflammatory cytokines expression. Ubiquitination modification has been reported to play great roles in NF-κB activation, and multiple studies showed that ubiquitination regulation is essential for the regulation of progression of PA keratitis [7,8]. In the present research, we found USP22 could remove K48 linked polyubiquitination chain of TRAF6, which is the key adaptor of NF-κB signaling pathway, leading to the stability of TRAF6, and therefore promote NF-κB activation and the downstream pro-inflammatory cytokines production.…”

“…If the substrate is modified by lysine 48(K48) ubiquitin, the target protein will be degraded by proteasome system [6]. Recently, many studies already showed that ubiquitination process is crucial for the is regulation of inflammatory responses in PA-induced keratitis [7,8].…”

NLRC3 negatively regulates CD4+ T cells and impacts protective immunity during Mycobacterium tuberculosis infection

“…NLRC3, an intracellular member of NLR family, has been reported to be expressed by various immune cell populations, including macrophages, epithelial cell and T cells and suppress inflammatory signaling pathways in innate immune cells [15–20]. These pathways include the NF-κB and STING pathways, which are exploited by bacteria or viruses to evade the host immune response and to promote survival [15,16].…”

miR‐190b promotes tumor growth and metastasis via suppressing NLRC3 in bladder carcinoma

“…For example, Hu et al reported that NLRC3 negatively regulates CD4+ T cells and impacts protective immunity during Mycobacterium tuberculosis infection . Guo et al demonstrated that NLRC3 promotes host resistance against Pseudomonas aeruginosa ‐induced keratitis by promoting the degradation of interleukin 1 receptor associated kinase 1 (IRAK1) . Zha et al revealed that NLRC3 protected against monocrotaline (MCT)‐induced rat pulmonary hypertension (PH) and platelet‐derived growth factor‐BB (PDGF‐BB)‐induced PASMCs proliferation, migration, and inflammation through a mechanism involving PI3K inhibition .…”