Heat shock protein 60 from Chlamydia pneumoniae elicits an unusual set of inflammatory responses via Toll-like receptor 2 and 4 in vivo.
ABSTRACT Heat shock protein 60 (HSP60) from Chlamydia pneumoniae was described to trigger in vitro inflammatory and cytokine responses including TNF and IL-12p40. Although it can be found in atherosclerotic plaques of patients, the stimulatory potential of chlamydial and other HSP60 in vivo is unclear. We now report that chlamydial HSP60 fails to induce TNF expression in vivo, and significant serum levels of IL-12p40 are only found upon intraperitoneal injection of high doses of HSP60 or after intravenous application. Upon purification of chlamydial HSP60 with polymyxin B-agarose columns, its ability to induce TNF secretion in vitro is much reduced. However, purified chlamydial HSP60 causes increased serum levels of the CXC chemokines KC and MIP2 in vivo, as well as a strong accumulation of polymorphonuclear neutrophils (PMN) in the peritoneal cavity upon intraperitoneal challenge. With respect to PMN accumulation, chlamydial HSP60 is more potent than endotoxin or the CpG oligonucleotide 1668. The responses observed are completely abolished in Toll-like receptor (TLR)2/4-double-deficient mice, while single-deficient mice respond almost normally. Furthermore, KC induction and PMN accumulation are largely dependent on MyD88. In conclusion, HSP60 from C. pneumoniae triggers inflammatory responses in vivo that differ from responses induced by endotoxin or CpG oligonucleotides and are dependent on TLR2 and 4.
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ABSTRACT: The innate immune system is a critical part of the response to pathogens and overall immunity. Compared with the adaptive immune response, these innate responses are not antigen-specific and recognize patterns in bacteria, viruses and fungi. Chief among these are TLRs (Toll-like receptors). TLRs are PRRs (pattern recognition receptors) that are germ-line-encoded and are also able to recognize endogenous molecules that are released upon cell damage or stress and have been demonstrated to have a key role in numerous autoimmune diseases, including RA (rheumatoid arthritis) and SSc (systemic sclerosis). SSc is an autoimmune disorder in which vascular injury occurs and there is a chronic low-grade inflammation followed by excessive ECM (extracellular matrix) deposition and ultimately fibrosis. The fibrosis ultimately leads to organ dysfunction and death. The preceding vascular damage and activation of the innate immune system leads to mobilization of the innate lymphoid cells and the up-regulation of multiple genes and pro-fibrotic cytokines. These locally released cytokines activate resident fibroblasts to differentiate into myofibroblasts. The aim of the present review is to explore the role of the innate immune system in SSc and TLRs and how these interact with stromal cells to produce fibrosis. Targeting the innate immune system or specific components of the TLR signalling cascade may be a novel therapeutic option in what is an incurable disease.Clinical Science 03/2014; 126(5):329-37. · 4.86 Impact Factor
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ABSTRACT: Acute respiratory tract infection (RTI) is a leading cause of morbidity and mortality worldwide and the majority of RTIs are caused by viruses, among which respiratory syncytial virus (RSV) and the closely related human metapneumovirus (hMPV) figure prominently. Host innate immune response has been implicated in recognition, protection and immune pathological mechanisms. Host-viral interactions are generally initiated via host recognition of pathogen-associated molecular patterns (PAMPs) of the virus. This recognition occurs through host pattern recognition receptors (PRRs) which are expressed on innate immune cells such as epithelial cells, dendritic cells, macrophages and neutrophils. Multiple PRR families, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), contribute significantly to viral detection, leading to induction of cytokines, chemokines and type I interferons (IFNs), which subsequently facilitate the eradication of the virus. This review focuses on the current literature on RSV and hMPV infection and the role of PRRs in establishing/mediating the infection in both in vitro and in vivo models. A better understanding of the complex interplay between these two viruses and host PRRs might lead to efficient prophylactic and therapeutic treatments, as well as the development of adequate vaccines.Pathogens. 06/2013; 2(2).
- Revista colombiana de obstetricia y ginecología 12/2012; 63(4):346-355.