How inflammatory resolution shapes long-term tissue immunity

Inflammation is a protective response to infection and injury. However, once its job is done it's imperative that inflammation then switches off. This can be best exemplified by a bee sting where skin becomes hot, red, swollen and painful, the so-called four cardinal signs of inflammation. However, within hours or certainly a day, the heat, redness, swelling and pain goes away. This latter process is called inflammatory resolution. Importantly, resolution of acute inflammation is a natural sequence of events that, until now, was believed to lead the affected tissues back to the physiological and immunological state they experienced before inflammation occurred.

However, we propose that this is not the case, and that resolution triggers a series of local clinically silent, but immunologically active events that are essential for maintaining the long-term immune health and well-being of the infected/damaged tissue. The aim of this proposal, therefore, is to study these novel post-inflammatory resolution processes and understand how they immunologically enhance tissues for prolonged and improved immune protection. The experiments proposed here will describe a new area of immune activity that extends long after the outwards sign of heat, redness, swelling and pain have resolved with a key role in maintaining lifelong heathy ageing and well-being in terms of shaping more efficient responses to secondary and subsequent infections.

Consequently, it will describe new immune processes whose dysregulation arising from old age, pathogenic infections, environmental influences may become dysregulated driving aberrant immune responses and shortening human and animal life span. Consequently, we envision using this knowledge to optimise immune responses to infection without the need for antimicrobials and the problems of antimicrobial resistance.

Resolution of inflammation is believed to result in the affected tissue retuning back to the physiological state it experienced before the infection/injury. However, we discovered that following the resolution of S. pneumoniae-induced lung inflammation there is the re-infiltration of mononuclear phagocytes and lymphocytes that limit tissue injury and bolster long-term tissue immunity.

Transcriptomic analysis of post-resolution macrophage populations compared to macrophages from naïve lung revealed that the most abundantly enriched genes were those that encoded proteins for (1) lymphocyte chemotaxis, (2) positive regulation of T cell differentiation as well as (3) factors that control mononuclear cell migration.

Hence, we hypothesise that this is a novel phase of immune activity that shapes long-term tissue immunity and preserves tissue integrity post resolution driven, at least in part, by re-infiltrating post-resolution macrophages.

To investigate this, we propose single cell transcriptomics complemented with spatial transcriptomics to build an immune map of resolution and post-resolution biology of mouse lung infected with resolving S. pneumoniae. We will then use fate mapping mice to trace macrophage populations that repopulate the lung once inflammation has resolved and determine their tissue sub-localisation relative to other immune cells. Finally, we will use pharmacological tools and conditional knocked out mice to delete, in a time and tissue dependent manner pathways most enriched in post-resolution macrophages and determine the impact on long-term tissue immunity.

This under-studied area of inflammation research will describe a new phase of post-resolution immunology that will generate a wealth of data that will inform on how tissues control injury following inflammation whilst opening a new area of immune discovery that will identify signals that shape long-term tissue immunity following infection that maybe harnessed for drug development.