NOD-like receptors (NLRs) are cytosolic sensors which initiate innate immune responses against various stimulants. Some NLRs are a part of multiprotein complexes known as inflammasomes which lead to the activation of caspase-1 and subsequent production of IL-1? and IL-18. We unexpectedly identified that NLRP12 is a crucial mediator of lung inflammation in response to secondhand smoke (SHS). The proposed studies will address the role of NLRP12 in SHS-induced lung inflammation in both mice and humans. NLRP12 (aka NALP12/MONARCH-1/PYPAF-7), was the first NLR which was shown to induce IL-1? maturation via the interaction with ASC. Furthermore, a single report regarding the role of NLRP12 in bacterial recognition determined that NLRP12-deficient mice were more susceptible, showed enhanced bacterial burden in the spleen along with attenuated production of IL-18, IL-1?, and IFN-? after subcutaneous or intraperitoneal Yersinia pestis infection. In addition, a recent study involving human subjects demonstrated a crucial role of IL-1? in the pathophysiology of autoinflammatory syndromes also called NLRP12-associated disorders (NLRP12AD). However, the role of NLRP12 in secondhand smoke-induced COPD/emphysema has not been explored. Our preliminary data demonstrate that: 1) NLRP12 is upregulated in the COPD lungs;2) SHS exposure upregulates NLRP12 expression in human airway epithelial cells and human alveolar macrophages as well as murine lungs;3) as compared to other NLRs (NOD1, NOD2, NLRP1, NLRP3, and NLRC4), NLRP12 activation leads to much higher production of IL-1?, IL-18 and IL-17 in murine lungs following SHS exposure;4) SHS exposure causes reduced cellular recruitment to the lungs of NLRP12 KO mice;and 5) NLRP12 physically interacts with NOD2 (NLR involved in sensing of invasive microbes) and RIP2 (a common adaptor molecule for both TLRs and NLRs) in alveolar macrophages upon exposure to cigarette smoke extract (CSE) The central hypothesis of this proposal is that interaction of SHS with the host leads to NALP12 activation in the lung followed by IL-1?, IL-18 and IL-17 production which subsequently contributes to inflammation/emphysema.
The aims are: 1) to determine NALP12-dependent SHS-induced pulmonary inflammation in mice;2) to examine whether myeloid and/or resident cell expressed NALP12 contributes to SHS-induced lung inflammation;3) NALP12-dependent SHS extract-induced inflammatory responses in isolated human alveolar macrophages;and 4) to identify whether NLRP12 activation involves interaction with other cytosolic NLRs, potentially leading to inflammation and emphysema. Unique resources include NALP12 knockout mice and human alveolar macrophages. The R15 mechanism will help to train undergraduates including minority students in the field of emerging and devastating lung diseases such as COPD/Emphysema.

Public Health Relevance

While the burden of prevention of Secondhand smoke (SHS)-related disease rests firmly on the elimination of smoking, these diseases represent a threat to kids and adults of all ages. Though SHS is the most important risk factor for development of chronic obstructive pulmonary disease (COPD) and emphysema, the precise mechanisms by which this occurs remain elusive. The objective of the translational investigation is to define immunological pathways that regulate SHS mediated immune/inflammatory responses while minimizing extensive tissue damage during COPD and emphysema as novel targets for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-IMM-K (90))
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Humble, Michael C
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Louisiana State University A&M Col Baton Rouge
Schools of Veterinary Medicine
Baton Rouge
United States
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Cai, S; Batra, S; Del Piero, F et al. (2016) NLRP12 modulates host defense through IL-17A-CXCL1 axis. Mucosal Immunol 9:503-14
Cai, S; Batra, S; Langohr, I et al. (2016) IFN-γ induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense. Mucosal Immunol 9:718-29
Panday, Arvind; Sahoo, Malaya K; Osorio, Diana et al. (2015) NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol 12:5-23
Jin, Liliang; Batra, Sanjay; Douda, David Nobuhiro et al. (2014) CXCL1 contributes to host defense in polymicrobial sepsis via modulating T cell and neutrophil functions. J Immunol 193:3549-58