TLRs role in inflammation

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early events in the recognition of danger signals after tissue injury.

TLRs may serve as a bridge between innate and adaptive immune systems.

The systemic inflammatory response observed in the setting of overwhelming

infection bears striking similarities to that observed in the setting of severe

traumatic injury from a clinical and physiologic standpoint. Recent observations

have demonstrated that these disparate clinical entities share common mediators

on a molecular level. TLRs, specifically TLR4, and the endogenous molecule

high-mobility group box 1 are among the mediators that are known to play a role

in inflammation in the setting of sepsis. Evidence is accumulating that

demonstrates that these mediators also play a role in the host response to

tissue injury. Here, we highlight findings from the 7th World Conference on

Trauma, Shock, Inflammation and Sepsis in Munich, Germany, in the context of

this growing body of literature.

http://www.jleukbio.org/cgi/content/full/83/3/546

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TLRs, wound healing,and carcinogenesis 2009

Following acute injury, the concerted action of resident and nonresident cell

populations evokes wound healing responses that entail a temporary increase in

inflammation, extracellular matrix production, and proliferation to ultimately

restore normal organ architecture. However, chronic injury evokes a perpetuating

wound healing response promoting the development of fibrosis, organ failure, and

cancer. Recent evidence points toward toll-like receptors (TLRs) as important

regulators of inflammatory signals in wound healing. Here, we will review the

activation of TLRs by different endogenous and bacterial TLR ligands during

wound healing, and the contribution of TLR-induced signals to injury,

fibrogenesis, regeneration, and carcinogenesis. We will discuss the hypothesis

that TLRs act as sensors of danger signals in injured tissue to switch the wound

healing response toward fibrogenesis and regeneration as a protective response

to imminent danger at the cost of an increased long-term risk of developing

scars and cancer.

http://www.ncbi.nlm.nih.gov/pubmed/19089397?ordinalpos=1 & itool=EntrezSystem2.PEn\

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PATHOGEN RECOGNITION BY INNATE AMMUNITY 2006

Fungal Recognition by TLRs

The observation that Toll-deficient Drosophila are highly susceptible to fungal

infection led to the assumption that mammalian TLRs also participate in

antifungal immunity. Several fungal PAMPs located in the cell wall or on the

cell surface of fungi are recognized by TLR2 or TLR4.

The Th1 response is critical in protection against fungi. Although TLR-mediated

signals mostly induce Th1-directed responses, activation of TLR2 is less

inflammatory and favors the development of the Th2 response through the

induction of IL-10 (Agrawal et al., 2003). Indeed, in vivo infection experiments

using mutant mice suggest differential roles of TLR2 and TLR4 in fungal

infection. TLR4 & #8722;/ & #8722; mice showed increased susceptibility to

disseminated Candida infection, whereas TLR2 & #8722;/ & #8722; mice showed

increased resistance (Netea et al., 2004). Infected TLR2 & #8722;/ & #8722; mice

showed normal production of inflammatory cytokines such as TNF and IL-1 but

severe impairment in IL-10 production, indicating that C. albicans induces

immunosuppression through IL-10. A similar escape mechanism from the host

defense is also observed in A. fumigatus infection. A. fumigatus grows in two

forms, conidia and hyphae. TLR2 and TLR4 both recognize conidia, whereas the

hyphae are only recognized by TLR2; thus, the phenotypic switch to hyphae from

conidia results in the release of IL-10, which impairs the cellular immune

response necessary for the Aspergillus clearance.

Dectin-1 is a type II transmembrane protein with a C type lectin domain in the

extracellular region and an ITAM motif in the intracellular domain. Dectin-1

binds â-glucan and is the primary receptor on macrophages for phagocytosis of

various fungi (Brown et al., 2002). It has been demonstrated that dectin-1 can

collaborate with TLR2 in response to yeast to elicit a strong inflammatory

response via recruitment of the protein tyrosine kinase Syk ([Gantner et al.,

2003], [ et al., 2005] and Underhill et al., 2005 D.M. Underhill, E.

Rossnagle, C.A. Lowell and R.M. , Dectin-1 activates Syk tyrosine kinase

in a dynamic subset of macrophages for reactive oxygen production, Blood 106

(2005), pp. 2543–2550. View Record in Scopus | Cited By in Scopus

(104)[underhill et al., 2005]). However, although â-glucan is presented during

C. albicans yeast growth, it is not presented during filamentous growth. As a

consequence, dectin-1-mediated antimicrobial defenses are not effective against

filaments, which may explain why filaments are more virulent. In addition to

dectin-1, other receptors such as the type 3 complement receptor, the mannose

receptor, and DC-SIGN are implicated in the recognition and phagocytosis of

Candida (Takahara et al., 2004

escape of pathogens from innate immune recognition

Bacteria and fungi are also able to exploit the TLR system to evade host immune

responses. Certain pathogens have modified forms of the normal TLR ligands, such

as the LPSs from H. pylori, P. gingivalis, and L. pneumophila and flagellin of

H. pylori and C. jejuni (Andersen-Nissen et al., 2005). Some pathogens modify

the TLR signaling pathways for their benefits. M. tuberculosis avoids being

killed by macrophages by inhibiting IFN-ã-mediated signaling. Prolonged

signaling with a 19 kDa lipoprotein from Mycobacterium, which stimulates TLR2,

inhibits IFN-ã production and major histocompatibility complex (MHC) class II

antigen-processing activity ([Fortune et al., 2004] and [Pai et al., 2003]).

These findings suggest that, at least in part, persistent TLR2 signaling enables

Mycobacterium to evade T cell responses and persist as a long-term infection.

Similarly, pathogenic Yersinia species release V antigen (LcrV), a virulence

factor that stimulates the production of IL-10 via TLR2 and suppresses

production of TNF and IFN-ã. As a consequence, TLR2 & #8722;/ & #8722; mice are

actually less susceptible to oral infection with Yersinia enterocolitica (Sing

et al., 2002 A. Sing, D. Rost, N. Tvardovskaia, A. Roggenkamp, A. Wiedemann,

C.J. Kirschning, M. Aepfelbacher and J. Heesemann, Yersinia V-antigen exploits

toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression, J.

Exp. Med. 196 (2002), pp. 1017–1024. View Record in Scopus | Cited By in Scopus

(176)Sing et al., 2002

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The impact of endogenous triggers on trauma-associated inflammation.

Zedler S, Faist E.

Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Department of

Surgery, Munich, Germany.

PURPOSE OF REVIEW: Inflammation immediately starting after trauma is a

consequence of an efficient host defense system that is not only capable of

sensing exogenous and pathogen-derived danger signals, but also endogenous,

multifunctional alarm signals, which both can initiate an inflammatory response.

RECENT FINDINGS: Even in the absence of infection, Toll-like receptors play an

important role in inflammation via recognition of host-derived, endogenous

'damage signals' like heat shock proteins and 'alarmins' such as the nuclear

protein high-mobility group box protein 1, which are presented as a result of

tissue trauma. In addition to the Toll-like receptors, a number of other

receptors are involved in the host inflammatory response, including the new

family of nucleotide oligomerization domain-like receptors capable of sensing

the presence of danger signals in the cytoplasm. Important links occur between

the Toll-like receptors as key inducers of the pro-forms of interleukin-1beta

and interleukin-18 and the activation of certain nucleotide oligomerization

domain-like receptors, resulting in inflammasome formation--an essential process

leading to the secretion of these proinflammatory cytokines. SUMMARY: In

addition to improved insights into the regulation of traumatic inflammation and

the etiology of the systemic inflammatory response syndrome, some endogenous

immune triggers seem to have the potential to serve as novel biomarkers in

predicting post-traumatic complications.

http://www.ncbi.nlm.nih.gov/pubmed/17077693?ordinalpos=1 & itool=EntrezSystem2.PEn\

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