Abstract
Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by excessive inflammation and are exacerbated by nontypeable Haemophilus influenzae (NTHi). Airway epithelial cells mount the initial innate immune responses to invading pathogens and thus modulate inflammation. While inflammation is necessary to eliminate a pathogen, excessive inflammation can cause damage to the host tissue. Therefore, the inflammatory response must be tightly regulated and deciphering the signaling pathways involved in this response will enhance our understanding of the regulation of the host inflammatory response. NTHi binds to TLR2 and signal propagation requires the adaptor molecule myeloid differentiation factor 88 (MyD88). An alternative spliced form of MyD88 is called MyD88 short (MyD88s) and has been identified in macrophages and embryonic cell lines as a negative regulator of inflammation. However, the role of MyD88s in NTHi-induced inflammation in airway epithelial cells remains unknown. Here we show that NTHi induces MyD88s expression and MyD88s is a negative regulator of inflammation in airway epithelial cells. We further demonstrate that MyD88s is positively regulated by IKKβ and CREB and negatively regulated by ERK1/2 signaling pathways. Taken together these data indicate that airway inflammation is controlled in a negative feedback manner involving MyD88s and suggest that airway epithelial cells are essential to maintain immune homeostasis.
Highlights
Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) affect more than one-half billion people globally
myeloid differentiation factor 88 (MyD88) Small Interfering RNA (siRNA) significantly enhanced Nontypeable Haemophilus influenzae (NTHi)-induced NF-κB luciferase activity (Fig 2F), and increased NTHiinduced expression of IL-6 and IL-1β (Fig 2G). Together these results show that MyD88s is a negative regulator of NTHi-induced inflammation
We showed that NTHi induces expression of MyD88s in airway epithelial cells and in the lung of mice
Summary
Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) affect more than one-half billion people globally. These diseases are characterized by inflammation and are exacerbated by respiratory pathogens [1,2,3]. Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative, non-encapsulated, opportunistic coccobacillus and the most. NTHi is a major cause of airway inflammation during stable and exacerbated states of COPD. In addition to COPD exacerbations, NTHi causes other respiratory diseases such as chronic bronchitis [4, 5]. The increasing numbers of antibiotic resistant strains presents an urgent need for the development of novel non-antibiotic therapeutic [6, 7]
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