LPS Guides Distinct Patterns of Training and Tolerance in Mast Cells

Abstract

Mast cells (MCs) are tissue-resident, long lived innate immune cells with important effector and immunomodulatory functions. They are equipped with an eclectic variety of receptors that enable them to sense multiple stimuli and to generate specific responses according on the type, strength and duration of the stimulation. Several studies demonstrated that myeloid cells can retain immunological memory of their encounters – a process termed ‘trained immunity’ or ‘innate immune memory’. As MCs are among the one of first cells to come into contact with the external environment, it is possible that such mechanisms of innate immune memory might help shaping their phenotype and effector functions; however, studies on this aspect of MC biology are still scarce. In this manuscript, we investigated the ability of MCs primed with different stimuli to respond to a second stimulation with the same or different ligands, and determined the molecular and epigenetic drivers of these responses. Our results showed that, while the stimulation with IgE and β-glucan failed to induce either tolerant or trained phenotypes, LPS conditioning was able to induce a profound and long-lasting remodeling of the signaling pathways involved in the response against LPS or fungal pathogens. On one side, LPS induced a strong state of unresponsiveness to secondary LPS stimulation due to the impairment of the PI3K-AKT signaling pathway, which resulted in the reduced activation of NF-κB and the decreased release of TNF-α and IL-6, compared to naïve MCs. On the other side, LPS primed MCs showed an increased release of TNF-α upon fungal infection with live Candida albicans, thus suggesting a dual role of LPS in inducing both tolerance and training phenotypes depending on the secondary challenge. Interestingly, the inhibition of HDAC during LPS stimulation partially restored the response of LPS-primed MCs to a secondary challenge with LPS, but failed to revert the increased cytokine production of these cells in response to C. albicans. These data indicate that MCs, as other innate immune cells, can develop innate immune memory, and that different stimulatory environments can shape and direct MC specific responses towards the dampening or the propagation of the local inflammatory response.

Training vs. Tolerance: The Yin/Yang of the Innate Immune System

“…C. albicans as well as β-glucan induce a functional reprogramming of innate immune cells, resulting in enhanced release of pro-inflammatory mediators (i.e., IL-1β, TNF-α, IL-6, IL-32 and ROS) mediated by an IL-1-dependent signaling [ 58 , 59 , 62 ]. Similarly, LPS guides the induction of training or tolerance depending on the type of secondary stimulus [ 65 ].…”

Trained immunity in type 2 immune responses

“…LTB 4 , a major lipid mediator produced by alveolar macrophages and neutrophils, is highly chemotactic for MC progenitors and the responsiveness to LTB 4 inversely correlates with MC maturation 141 . MCs are long-lived cells, however, so far studies investigating trained immunity in mast cells have focused predominately on endotoxin priming and infection models 142 . Potential trained immunity programs in constitutive MCs and/or BM-derived mucosal MCs in the context of type 2 inflammation remains to be elucidated.…”

Endotoxin tolerance and trained immunity: breaking down immunological memory barriers

“…Along these lines, the stimulation of mast cells with LPS leads to a reduced cytokines production upon secondary endotoxin challenge, reproducing ET. Nevertheless, when C. albicans was used as heterologous challenge, TNFα release was enhanced, reminiscent of TI ( 140 ). How this TLR4 stimulation gives rise to both training and tolerance depending on the second insult is not understood, but the ET phenotype was sensitive to histone deacetylases inhibition ( 140 ).…”

“…Nevertheless, when C. albicans was used as heterologous challenge, TNFα release was enhanced, reminiscent of TI ( 140 ). How this TLR4 stimulation gives rise to both training and tolerance depending on the second insult is not understood, but the ET phenotype was sensitive to histone deacetylases inhibition ( 140 ). These findings suggest a potential “double-edged sword” role for TLR4, with its effect varying depending on the secondary stimulation.…”