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Appropriate production of mucous plays a critical role in host innate mucosal defenses against infection. However, if uncontrolled, excessive mucous may be detrimental to the host. Mucous production thus must be tightly regulated. In the present study, we investigate the role of RIP-2 in regulating nontypeable Haemophilus influenzae (NTHi)-induced up-regulation of mucin MUC5AC expression. We show that RIP-2 is a negative regulator of MUC5AC, whereas MAP kinase JNK acts as a positive regulator for MUC5AC induction by NTHi. Our studies unveil a novel role for RIP-2 in controlling mucous production in upper respiratory disease and may shed light on the identification of new therapeutic targets. Introduction Mucosal barriers in the upper respiratory tract, including the middle ear, typically aide in trapping and clearance of infectious agents as a protective mechanism for the host [1]. Mucins are a major component of mucous in these regions. Mucins are a family of high molecular weight glycoproteins secreted by goblet cells in mucosal tissues. There are more than 20 known mucins, twelve of which have been found in the respiratory tract [2]. Mucin 5AC (MUC5AC) is known to be one of the major mucins produced during upper respiratory infections, including otitis media (OM). While appropriate mucous production is protective for the host, excessive mucous production can be deleterious [1-4]. In fact, thick mucous and neutrophil nets can create a biofilmlike environment for nontypeable Haemophilus influenzae (NTHi), one of the major bacterial pathogens of OM and chronic obstructive pulmonary disease (COPD). Overproduction of mucin MUC5AC can lead to persistent, chronic infections or can worsen acute tissue injury [1, 5]. Therefore, like inflammation, mucous production must be tightly controlled. NTHi-caused upper respiratory infections, including COPD and OM, remain major health problems worldwide. COPD is the third leading cause of death in the U.S. with numbers rising each year. Hassett et al. reported the annual number of Americans affected by COPD in 2014 at over 14 million [6]. OM is the most common pediatric infectious disease in humans accounting for over 20 million physician visits and costing the U.S. upwards of 5 billion dollars annually [7, 8]. OM is characterized by mucous overproduction and inflammation in the middle ear cavity due to infection. Pediatric patients are highly susceptible to OM pathogens due to the shortened length of the Eustachian tube during development [7]. Currently, the standard treatment for both COPD and OM is systemically administered broad-spectrum antibiotics, which, leads to increased antibiotic resistance. Surgical intervention is also frequently utilized in pediatric OM patients by placing tubes to aid in drainage of the middle ear cavity. This commonplace surgical intervention and frequent use of antibiotics warrants concern for the development of drug-resistant strains of bacteria as well as the rising healthcare costs associated with both inflammatory diseases. Therefore, development of non-antibiotic therapeutic strategies is urgently needed based on a full understanding of the molecular pathogenesis of these inflammatory diseases. Receptor interacting protein-2 (RIP-2) plays a key role in activation and regulation of multiple inflammatory signaling cascades, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK). Nucleotide-binding oligomerization domain 2 (NOD2) is a cytosolic receptor that detects bacterial peptidoglycans and other inflammatory stimuli [9]. Upon NOD2 detection of pathogenassociated molecular patterns (PAMPs), RIP-2 is recruited and interacts via CARD-CARD interactions. RIP-2 is a dual-specificity kinase downstream of NOD-like receptors, which undergoes autophosphorylation and subsequent polyubiquitination to drive transcription of inflammatory cytokines and chemokines [9]. RIP2 is an essential signaling adaptor, and previous studies have shown NF-κB activation is sub-optimal in its absence [10]. Previous studies have also shown that RIP-2 acts as an important adaptor molecule for ovalbumin-induced lung inflammation. However, the role of RIP-2 in bacteria-induced expression of mucin MUC5AC, a major contributor of OM and COPD pathology, remains largely unknown. In the present study, we sought to investigate the role of RIP-2 in NTHi-induced MUC5AC gene expression. Here we show that NTHi induces RIP-2 expression at mRNA and protein levels, and RIP-2 is a Correspondence to: Dr. Jian-Dong Li, Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA 30303, USA, Tel: 404-413-3574; Fax: 404413-3580; E-mail: jdli@gsu.edu

Receptor Interacting Protein-2 acts as negative regulator for nontypeable Haemophilus influenzae-induced mucin MUC5AC expression