Infection, immunity and the neuroendocrine response

Abstract

The Central Nervous (CNS) and Immune Systems (IS) are the two major adaptive systems which respond rapidly to numerous challenges that are able to compromise health. The defensive response strictly linking innate to acquired immunity, works continuously to limit pathogen invasion and damage. The efficiency of the innate response is crucial for survival and for an optimum priming of acquired immunity. During infection, the immune response is modulated by an integrated neuro-immune network which potentiates innate immunity, controls potential harmful effects and also addresses metabolic and nutritional modifications supporting immune function. In the last decade much knowledge has been gained on the molecular signals that orchestrate this integrated adaptive response, with focus on the systemic mediators which have a crucial role in driving and controlling an efficient protective response. These mediators are also able to signal alterations and control pathway dysfunctions which may be involved in the persistence and/or overexpression of inflammation that may lead to tissue damage and to a negative metabolic impact, causing retarded growth. This review aims to describe some important signalling pathways which drive bidirectional communication between the Immune and Nervous Systems during infection. Particular emphasis is placed on pro-inflammatory cytokines, immunomodulator hormones such as Glucocorticoids (GCs), Growth hormone (GH), Insulin-like Growth Factor-1 (IGF-1), and Leptin, as well as nutritional factors such as Zinc (Zn). Finally, the review includes up-to-date information on this neuroimmune cross-talk in domestic animals. Data in domestic animal species are still limited, but there are several exciting areas of research, like the potential interaction pathways between mediators (i.e. cytokine-HPA regulation, IL-6-GCS-Zn, cytokines-GH/IGF-1, IL-6-GH-Leptin and thymus activity) that are or could be promising topics of future research in veterinary medicine.

Fig. 1

Main organs and signalling pathways in bidirectional communication between Immune and Neuroendocrine Systems: pro-inflammatory cytokines, HPA and the somatotropic axis, thymus activity and adipose tissue hormones (see the text for explanation) (Webster and Sternberg, 2004, Mocchegiani et al., 2006, Sternberg, 2006, Gabler and Spurlock, 2008, Elenkov, 2008).

Fig. 2

Main immune and neuroendocrine signals during the APR (see text for explanation).

Fig. 3

Possible pathways involved in controlled immune response or in uncontrolled inflammation: the central role of pro-inflammatory cytokine levels and glucocorticoids. (a) IL-1, TNF-α and IL-6 production sustains an early and efficient inflammatory/innate response which limits and destroys the pathogen and primes acquired immunity; glucocorticoids (GCs) control the local and systemic inflammatory response preventing damage by excessive inflammation; (b) uncoupled regulatory linkage between GH and IGF-1 during infection: increased levels of GH could be considered as a compensatory attempt to sustain innate immunity and counteract excessive GC activity; (c) reduced GH and IGF-1 activity drives metabolic and nutritional modifications towards supporting the immune function; cytokine production in adipose and muscle tissue can favour energy partitioning; (d) uncontrolled high levels of pro-inflammatory cytokines, IL-1, TNF-α particularly IL-6, cause inflammatory tissue damage concomitantly with (e) HPA axis dysregulation, altered levels of ACTH and/or GCs and reduced GCs Receptor (GR) expression; (f) persistent levels of IL-6 mediate chronic inflammation (Calcagni and Elenkov, 2006; Heemsherk et al., 2001; Sternberg, 2006, Heijnen, 2007, Pace et al., 2007, Elenkov, 2008, Webster et al., 2002, Webster and Sternberg, 2004, Gabay, 2006, Gabler and Spurlock, 2008, Quinn, 2008).

Fig. 4

Possible pathways contributing to immunosuppression and catabolic state in persistent infection and sepsis. (a) Excessive and chronic production of cytokines induces overactivation of HPA; (b) persistent levels of IL-6 and of GCs induce immunosuppressive effects by impairing Th1 immunity and zinc bioavailability; (c) High GCs and pro-inflammatory cytokines exert tissue catabolic effect; (d) pro-inflammatory cytokine levels lead to muscle and liver GH resistance and the inhibition of IGF-1 activity (see the text); (e) high levels of anti-inflammatory mediators such as IL-10 contributes to immunesuppression with an increased risk of bacterial overinfection. (Spurlock, 1997, Briard et al., 2000, Heemskerk et al., 1999, Frost and Lang, 2004, Ashare et al., 2005, Mocchegiani et al., 2006, Mocchegiani et al., 2007, Cooney and Shumate, 2006).