Inflammation: Mechanisms, Costs, and Natural Variation

Inflammation is a pervasive phenomenon that operates during severe perturbations of homeostasis, such as infection, injury, and exposure to contaminants, and is triggered by innate immune receptors that recognize pathogens and damaged cells. Among vertebrates, the inflammatory cascade is a complex network of immunological, physiological, and behavioral events that are coordinated by cytokines, immune signalingmolecules. Although themolecular basis of inflammation is well studied, its role in mediating the outcome of host-parasite interactions has received minimal attention by ecologists. This review provides a synopsis of vertebrate inflammation, its life-history modulation, and its effects upon host-pathogen dynamics as well as hostcommensal microbiota interactions in the gut. What emerges is evidence for phenotypic plasticity of inflammatory responses despite the apparently invariant and redundant nature of the immunoregulatory networks that regulate them. 385 A nn u. R ev . E co l. E vo l. Sy st . 2 01 2. 43 :3 85 -4 06 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g by W es te rn K en tu ck y U ni ve rs ity H el m C ra ve ns L ib ra ry o n 11 /0 9/ 12 . F or p er so na l u se o nl y. ES43CH18-Ashley ARI 1 October 2012 12:33 Virulence: damage to a host arising from extraction of resources by a pathogenic infection or collateral damage produced by the host’s immune response INTRODUCTION Inflammation is a pervasive form of defense that is broadly defined as a nonspecific response to tissue malfunction and is employed by both innate and adaptive immune systems to combat pathogenic intruders. A distinctive feature of inflammatory responses in relation to other facets of antiparasite defenses is that damage to the self is unavoidable. Importantly, collateral damage from inflammation is not the same as immunopathology, which involves a specific immune-mediated attack on target tissue that is no longer recognized by the immune system as self. Autoimmune pathology reflects dysregulation of adaptive immune components, such as antibody and cellmediated functions, and has both genetic and environmental influences (Graham et al. 2005, Råberg et al. 1998). Although inflammation-induced collateral damage can certainly contribute to immunopathology (e.g., rheumatoid arthritis, multiple sclerosis, diabetes), the damage invoked by inflammation represents a basic biological trade-off between damage control and self-maintenance and does not require the presence of self-antigens to become activated. The emergence of the field of ecoimmunology has spurred a renewed interest in quantifying and understanding variation of immune function, which has traditionally been under the purview of cellular and molecular immunologists. However, the major difference of this relatively new field involves the assessment of immunity in nonmodel organisms in their natural environment, which has been challenging and biased toward measurement of the adaptive immune system. Ecoimmunologists are also interested in the fitness costs of immunity. A major hurdle of ecoimmunology has been integrating host immune function with host-pathogen dynamics and disease ecology (Graham et al. 2011, Hawley & Altizer 2010). In effect, studies have quantified immune function in a vacuum without assessing how these measures relate to disease resistance. Lastly, the importance of inflammation in regulating the outcome of host-pathogen interactions has received minimal attention by ecologists (Sears et al. 2011, Sorci & Faivre 2009). This review provides an overview of inflammation and its role in mediating the ecology and evolution of host-parasite and host-commensal interactions. This review primarily focuses on inflammation in vertebrates, though we draw upon several studies among invertebrates. Although themolecular basis of inflammation is well described, we provide basic definitions of inflammation, a synopsis of inflammatory pathways, and the types of inflammatory response to provide ecologists and evolutionary biologists with proximatemechanisms that inform ultimate levels of analysis.We then present studies demonstrating life-history variation of inflammatory responses, in particular seasonal and latitudinal variation, as well as trade-offs with reproduction. Inflammation also affects both the host and pathogen, and we review the evidence that host-pathogen dynamics can be altered, such as virulence and transmission. Throughout this review, we refer to pathogen and parasite interchangeably, which we define as infectious agents that have the capability to harm hosts. The regulation of inflammation also shapes host-commensal interactions in the vertebrate gut. Such interactions benefit commensal organisms, whereas the host species neither benefits nor is harmed. The selective forces governing host-microbiota interactions in the gut is a rapidly developing field that has received minimal input from evolutionary ecologists. WHAT IS INFLAMMATION? Inflammation is a biological reaction to a disrupted tissue homeostasis (Medzhitov 2008). At its basic level, it is a tissue-destroying process that involves the recruitment of blood-derived products, such as plasma proteins, fluid, and leukocytes, into perturbed tissue. This migration is facilitated by alterations in the local vasculature that lead to vasodilation, increased vascular permeability, and increased blood flow. 386 Ashley et al. A nn u. R ev . E co l. E vo l. Sy st . 2 01 2. 43 :3 85 -4 06 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g by W es te rn K en tu ck y U ni ve rs ity H el m C ra ve ns L ib ra ry o n 11 /0 9/ 12 . F or p er so na l u se o nl y. ES43CH18-Ashley ARI 1 October 2012 12:33 Cytokines: soluble proteins of low molecular weight that modulate the differentiation, proliferation, and function of immune cells, and coordinate inflammatory responses DAMP: damageassociated molecular pattern Infection by microbial invaders is often implicated as the major culprit that promotes inflammatory responses (Figure 1a). However, injury or trauma (in the absence of parasitic infection) and exposure to foreign particles/irritants/pollutants are also potent activators of inflammation (Medzhitov 2008), suggesting that this response likely evolved as a general adaptation for coping with damaged or malfunctioning tissue (Matzinger 2002). A common explanation for why infection and trauma might evoke similar inflammatory responses is that infection often follows wounding, which implies that it would be advantageous to respond to trauma as if infection occurred (Nathan 2002). The more parsimonious explanation is that both pathogens and wounding cause damage to cells and tissue and trigger similar responses (Bianchi 2007). The primary functions of inflammation are to rapidly destroy or isolate the underlying source of the disturbance, remove damaged tissue, and then restore tissue homeostasis (Medzhitov 2008, Soehnlein & Lindbon 2010). Inflammation, when regulated properly, is putatively adaptive. This statement is supported by the increased risk of serious infections in humans with genetic deficiencies in primary components of inflammation, such as neutropenia (abnormally low level of circulating neutrophils). Defects in the genes that encode proinflammatory cytokines and effectors of inflammation using mouse knock-out studies are also characterized by increased susceptibility to infection (Martinon et al. 2009). Conversely, there are several immune-relevant genes whose disruption leads to spontaneous inflammation, suggesting that the inflammatory response is actively suppressed by regulatory gene products to maintain health when inflammatory stimuli are not present (Nathan 2002). When not regulated properly, excessive inflammation can have devastating effects, resulting in excessive collateral damage and pathology. On an evolutionary level, inflammation is a highly conserved phenomenon and appears to be an important first line of defense for both invertebrates and vertebrates. Many of the components associated with the inflammatory cascade, such as chemotaxis and phagocytosis, are readily employed by unicellular organisms and were later co-opted as defensive mechanisms to maintain the integrity of more complex multicellular organisms (Rowley 1996). Innate immunity in the form of phagocytosis and antimicrobial peptides is present in the earliest of invertebrates, whereas the adaptive immune system evolved later and is unique to jawed vertebrates (Flajnik & Du Pasquier 2004). Adaptive immunity is hypothesized to have evolved to recognize and manage the complex communities of microbes that reside in the vertebrate digestive tract, which harbors a greater diversity of microbial fauna than the invertebrate gut (McFall-Ngai 2007). MECHANISMS OF INFLAMMATION Inflammation consists of a tightly regulated cascade of immunological, physiological, and behavioral processes that are orchestrated by soluble immune signaling molecules called cytokines. The first step of the inflammatory cascade involves recognition of infection or damage (Figure 1b). This is typically achieved by the detection of pathogen-associated molecular patterns (PAMPs), which are specifically directed toward general motifs of molecules expressed by pathogens that are essential for pathogen survival. Alarmins, or damage-associated molecular patterns (DAMPs), are endogenous molecules that signal damage or necrosis and are also recognized by the innate immune system. An advantage of detecting these signals is that inadvertent targeting of host cells and tissues is minimized. Unlike adaptive immunity, the innate immune system lacks the ability to distinguish among different strains of pathogens and whether such strains are virulent (harmful to the host) ( Janeway et al. 2005). Many damage signals are recognized by germ-line encoded receptors, such as transmembrane Toll-like receptors (TLRs) and intracellular nucleotide binding domain and leucine-rich-repeatcontaining receptors (NOD-like receptors or NLRs) (Lange et al. 2001, Proell et al. 2008, Roach www.annualreviews.org • Natural Variation of Inflammation 387 A nn u. R ev . E co l. E vo l. Sy st . 2 01 2. 43 :3 85 -4 06 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g by W es te rn K en tu ck y U ni ve rs ity H el m C ra ve ns L ib ra ry o n 11 /0 9/ 12 . F or p er so na l u se o nl y. ES43CH18-Ashley ARI 1 October 2012 12:33