Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

Abstract

Recent research links diet-induced obesity (DIO) with impaired immunity, although the underlying mechanisms remain unclear. We find that the induction of inducible NO synthase (iNOS) and cytokines is suppressed in mice with DIO and in bone marrow macrophages (BMM⌽) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMM⌽ from lean mice pretreated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMM⌽ from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMM⌽ from mice with DIO. This reduction is responsible for diminished NF-B activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMM⌽ from DIO mice whereas carboxy-terminal modulator protein (CTMP), a known suppressor of Akt phosphorylation, is elevated. This elevation stems from defective TLR2 signaling. In BMM⌽ from lean mice, both FFAs and TNF-␣-via separate pathways-induce an increase in CMTP. However, in BMM⌽ from DIO mice, TLR2 can no longer inhibit the TNF-␣-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMM⌽ from DIO mice. Thus, feeding mice a high-fat diet over time elevates the CTMP intracellular pool, initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-␣-induced CTMP. These findings unveil a link between obesity and innate immunity.O besity has been found to lead to diminished immune response. Several epidemiological studies of obese individuals found evidence of increased susceptibility to infections, including postoperative infectious complications (1), and a positive correlation between body weight index and the incidence of nosocomial infections (2). Diet-induced obesity (DIO) interferes with the ability of the immune system to appropriately respond to Porphyromonas gingivalis infection (3) and causes a higher mortality rate in mice following infection with influenza virus (4).Obesity is known to elevate TNF-␣ levels in the plasma of obese subjects (5, 6). However, macrophage functions are impaired in obese animals, with reduced phagocytic capacity and a defective oxidative burst (7,8). The reduced cytokine expression in response to infection observed in obese mice has been linked to a dysfunction in macrophages and/or a defect in maturation of monocytes (3,4,9). Moreover, the ability of mature macrophages from an obese individual to elicit an antimicrobial and cytotoxic response may be inhibited (10). Macrophages sense the presence of microorganisms via pattern recognition receptors, especially members of the Tolllike receptor (TLR) family, and subsequently activate proinflammatory signal pathways. TLR2 is an important receptor by which macrophages recognize P. gingivalis (11)(12)(13)(14), and mediates destructive chronic inflammatory reactions or confers host protection against P. gingivalis in acut...

A Humoral Immune Defect Distinguishes the Response to Staphylococcus aureus Infections in Mice with Obesity and Type 2 Diabetes from That in Mice with Type 1 Diabetes

“…Although T2D mice have an impaired adaptive immune response to S. aureus infection, T1D mice do not, indicating that this effect is T2D specific. It cannot be ruled out that impaired cellular defects that have been demonstrated elsewhere (14,31), specifically upstream of antigen presentation, are causative in re- duced antibody levels in T2D mice. However, increased total IgM levels in T2D mice at day 14 postinfection provide support for a B cell defect, specifically an impairment in class switching as opposed to a defect in antigen presentation.…”

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

“…Defects in the innate immune response to infection involving impaired macrophages (11)(12)(13) and/or neutrophils (14,15) have been described in this patient population. We have demonstrated in a mouse model of implant-associated osteomyelitis that obese/T2D mice have increased S. aureus infection severity compared to lean-fed control mice (16).…”

Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity

“…Feeding mice a high-fat diet (HFD) over time elevates the intracellular pool of a key innate immune inhibitory molecule, carboxyl-terminal modulator protein (CTMP), which inhibits Akt phosphorylation and attenuates innate immune responses in macrophages from DIO mice. The induction of CTMP is achieved initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-α-induced CTMP (9). Therefore, the elevation of CTMP by FFAs and TNF together with the disruption of TLR2 in macrophages is the key factor for the impairment of innate immune function in DIO mice.…”

“…In contrast, TLR2, which negatively modulates the TNF expression induced by FFAs, is dysfunctional in macrophages from DIO mice (9). Feeding mice a high-fat diet (HFD) over time elevates the intracellular pool of a key innate immune inhibitory molecule, carboxyl-terminal modulator protein (CTMP), which inhibits Akt phosphorylation and attenuates innate immune responses in macrophages from DIO mice.…”

“…Changes in immune functions have been proposed as underlying the pathogenesis of all these diseases. Obesity induces immune defects that lead to attenuated host responses to infection (7)(8)(9). The combination of dietary and exercise interventions has been proved to provide the most beneficial effects to obese people (10)(11)(12).…”