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Xtant literature suggests that pro-inflammatory cytokines serve as the downstream "effectors Xtant literature suggests that pro-inflammatory cytokines serve as the downstream "effectors" of the innate immune system by facilitating tissue repair within the heart. What has been less well understood, until recently, is how these myocardial innate immune responses are coordinated following tissue injury. The relatively recent discovery of a family of receptors termed Toll-like receptors (TLRs) and NOD-like receptors (NLRs) has greatly increased our understanding of the "upstream" molecular components that regulate the innate immune response.1 Moreover, recent studies have also indentified an important role for the complement system an essential component of the innate immune system in theAddress for Correspondence and Reprints: Douglas L. Mann, MD Division of Cardiology 660 S. Euclid Ave, Campus Box 8086 St. Louis, MO 63110 Phone: (314) 362-8908 Fax: (314) 454-5550 [email protected]. DISCLOSURE STATEMENT The author has no actual or potential conflict of interest with regard to this publication. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.MannPageheart.2 As will be discussed in the following focused review, recent insights into the role of TLRs have provided important new insights with respect to our understanding of the role inflammation in health and disease. TLRs serve as pattern recognition receptors (PRRs) that recognize conserved motifs on pathogens, so called pathogen-associated molecular patterns (PAMPs). Typical examples of pathogen-associated molecular patterns include the lipopolysaccharides (LPS) of Gramnegative organisms, the teichoic acids of Gram positive organisms, the glycolipids of mycobacterium, the zymosans of yeast, and the double-stranded RNAs of viruses (see Figure 1). These pathogen-associated molecular patterns are unique to these pathogens, and in some cases are required for their virulence. Thus, one of the quintessential features of the innate immune system is that it serves as an "early warning system" that enables the host to accurately and rapidly discriminate self from non-self. More recently it has become clear that TLRs also recognize molecular patterns of endogenous host material that is released during cellular injury or death, so-called damage associated molecular patterns (DAMPs).3,4 As shown in Figure 1, DAMPs can be derived from dying or injured cells, damaged extracellular matrix proteins or circulating oxidized proteins. This latter observation has provided a potentially important link between tissue injury, activation of pro-inflammatory mediators, and the resulting myocardial response to stress. The similarity of the biological response following TLR activation secondary to tissue injury and bacterial/viral infection likely represents a phylogenetically conserved host response, insofar as infection and tissue injury commonly occur together. Nonetheless, although the brisk and sometimes overwhelming inflammatory response at the time of tissue injury may have been the most effective and efficient means for the host to clear microorganisms at the site of tissue injury, i.