Innate immune response in acute critical illness: a narrative review

Abstract

Background: Activation of innate immunity is a first line of host defense during acute critical illness (ACI) that aims to contain injury and avoid tissue damages. Aberrant activation of innate immunity may also participate in the occurrence of organ failures during critical illness. This review aims to provide a narrative overview of recent advances in the field of innate immunity in critical illness, and to consider future potential therapeutic strategies.

Main text: Understanding the underlying biological concepts supporting therapeutic strategies modulating immune response is essential in decision-making. We will develop the multiple facets of innate immune response, especially its cellular aspects, and its interaction with other defense mechanisms. We will first describe the pathophysiological mechanisms of initiation of innate immune response and its implication during ACI. We will then develop the amplification of innate immunity mediated by multiple effectors. Our review will mainly focus on myeloid and lymphoid cellular effectors, the major actors involved in innate immune-mediated organ failure. We will third discuss the interaction and integration of innate immune response in a global view of host defense, thus considering interaction with non-immune cells through immunothrombosis, immunometabolism and long-term reprogramming via trained immunity. The last part of this review will focus on the specificities of the immune response in children and the older population.

Conclusions: Recent understanding of the innate immune response integrates immunity in a highly dynamic global vision of host response. A better knowledge of the implicated mechanisms and their tissue-compartmentalization allows to characterize the individual immune profile, and one day eventually, to develop individualized bench-to-bedside immunomodulation approaches as an adjuvant resuscitation strategy.

Keywords: Acute critical illness; Immunosenescence; Immunothrombosis; Innate immunity; Trained immunity.

Fig. 1

Innate immune response. Innate immune response is characterized by both proinflammatory (in red, top of the figure) and anti-inflammatory (in green, bottom of the figure) responses. Pro-inflammtory response can results in cellular damages forming DAMPs, that themselves trigger inflammation pathways. Anti-inflammatory response can induce immunoparalysis, resulting in secondary infections. The balance of this host response, its duration and its intensity are dependent of multiple factors: type of aggression on one hand, host factors (genetic, immune state, medical history, age …) on the other hand. C1 complement 1, DAMPs danger associated molecular patterns, DHA docosahexaenoic acid, EPA eicosapentaenoic acid, IL interleukin, NETosis release of NETs, Neutrophil Extracellular Traps, PAMPs pathogen associated molecular patterns, PLA2 phospholipase 2, ROS reactive oxygen species, TLR toll like receptor, TNF tumor necrosis factor

Fig. 2

Immunothrombosis in acute critical illness. Immunothrombosis is a local defense mechanism that can be dysregulated during ACI, inducing an hyper-inflammatory and hyper-oxidative state. Impaired immunothrombosis is notably mediated by neutrophils and endothelial dysfunction, activated leukocytes and platelets. Dysregulated immunothrombosis results in microthrombi formation, responsible of various organ dysfunction during ACI. MVs microvesicles, NETs neutrophil extracellular traps, ROS reactive oxygen species, TF tissue factor

Fig. 3

Innate immunity in aging patients. Balance between inflammatory and anti-inflammatory is highly modified in aging. The two main altered mechanisms are: a reduced capacity of response to injury by pro-inflammatory senescent cells (right) and a chronic systemic inflammation called inflammaging (left). CD cluster of differentiation, DNA desoxyribonucleic, IL interleukin, LT lymphocyte T, NK natural killer, ROS reactive oxygen species, SASP senescence-associated secretory phenotype, Th T helper, TLR toll like receptor, TNF tumor necrosis factor