Terms such as ‘immunoparalysis, immunosuppression, and anergy’ are far too extreme to describe the immune status of circulating leukocytes in patients with sepsis or SIRS. Altered immune status of circulating leukocytes is not globally present. Indeed, some functions like phagocytosis remain unaltered [
46], and
ex vivo cytokine production in response to heat-killed
S. aureus (HKSA) remains unchanged in patients with sepsis [
47] compared with healthy controls. This is in full agreement with the observation that LPS primes HKSA-induced TNF production in macrophage cell lines instead of leading to cross-tolerance [
48]. While the concept of endotoxin tolerance is considered to partially mimic the alteration of immune status in sepsis, it is worth mentioning that cross-tolerance between microbial agonists is not invariant. For example,
Candida albicans and fungal cell wall β-glucan also prime LPS-induced pro-inflammatory cytokine production [
49].
These observations led us to propose the concept of leukocyte reprogramming [
50] to explain the fact that tolerised macrophages retain anti-infectious properties. In addition, in tissues, there are numerous examples to illustrate the hyper-activity of these cells. For example, in mice with polymicrobial sepsis alone or as a ‘second hit’ after traumatic hemorrhage, it was nicely demonstrated by Chaudry’s group [
51] that the
ex vivo production of TNF or IL-6 after LPS activation was significantly reduced among peripheral blood mononuclear cells and splenic macrophages but that it was enhanced in alveolar and Kupffer cells. Similarly, in a murine model of trauma, the cytokine productive capacity of Kupffer cells and alveolar macrophages was enhanced [
52]. Indeed, macrophage functions differ depending on the compartment from which they derive. We established [
53] that the specific cytokine and cellular microenvironment within the lung was responsible for this particular resistance of alveolar macrophages to endotoxin tolerance, which can also be observed in human alveolar macrophages [
54]. Similarly, in kidneys, in response to a second challenge with LPS, the expression of TNF and inducible nitric oxide synthase was further enhanced [
55]. This may explain why unilateral nephrectomy could be protective in a murine peritonitis model and after LPS injection [
56]. Most importantly, despite the fashionable concept of M1/M2 macrophages, the response of macrophages to IL-4 and IFNγ is in fact completely different depending upon their origin [
57]. As a consequence of this great heterogeneity of immune cells within different compartments, each tissue behaves independently, contributing to the global inflammatory response with a specific pattern, as illustrated by differential cytokine expression in liver, lungs, heart, brain, muscle, kidney, intestine, and spleen [
58]. Another example of the different behavior of leukocytes in various compartments is the frequent occurrence of hemophagocytosis (>60%) directly observed in the bone marrow of the critically ill [
59]. This phenomenon is associated with extreme production of inflammatory cytokines. Accordingly, it has been proposed that when hemophagocytosis is diagnosed in critical care patients, aggressive immunosuppressive therapy be undertaken without delay [
59].
Differences between cells harvested from different compartments after sepsis have also been reported for spleen and peritoneal myeloid DCs [
60]. The major differences between compartments are further illustrated by the fact that gene deficiency may differentially affect outcomes of infection. For example, IL-10 deficiency protects against
Francisella tularensis pulmonary infection but aggravates cutaneous infection [
61]. Similarly, we showed that scavenger receptor-A (SR-A), ‘macrophage associated receptor with a collagenous base’ (MARCO), CD36, or TLR2 deficiency protect mice against peritoneal
S. aureus infection while these deficiencies aggravated pneumonia [
62]. Interestingly, when
Streptococcus pneumoniae was the pathogen used to colonize the murine nasopharynx, MARCO KO mice (but not SR-A KO mice) had significantly impaired clearance of pneumococcal colonization [
63].